This project seeks to study mechanisms by which tumor viruses or cellular genes contribute to oncogenesis and to devise approaches to prevent or reverse such changes in cells. Experiments with oncogenes have used various ras oncogenes and the ras containing Harvey sarcoma virus (Ha-MuSV). Yeast and mammalian ras genes have been shown to be functionally equivalent, since each can function in the heterologous system. Site directed mutagenesis has identified a cysteine residue near the C-terminus of all ras genes that is absolutely required for the transforming function of the protein, its membrane localization, and its binding of lipid. Variant Ha-MuSV that carry only one of the two point mutations present in the wild type Ha-MuSV are oncogenic, but not as oncogenic as the wild type virus. Non-coding sequences upstream and downstream from the ras coding sequences have a dramatic influence on the oncogenic activity of the virus. Papillomavirus research has been basic and clinical. Using frame shift and deletion mutagenesis, we have identified two genes in Bovine papillomavirus that can independently transform established mouse tissue culture cells. The protein product of one of these transforming genes has also been identified in transformed cells; this represents the first non-structural papillomavirus protein to be identified. A family with epidermodysplasia verruciformis (EV; widespread, chronic papillomavirus infection) has been identified in which EV is inherited as an X-linked recessive trait. Since familial EV usually displays an autosomal recessive inheritance pattern, our findings suggest that lesions in different chromosomes can lead to EV.